Epidermal growth factor potentiates EGFR(Y992/1173)-mediated therapeutic response of triple negative breast cancer cells to cold atmospheric plasma-activated medium.

Cold atmospheric plasma (CAP) holds promise as a cancer-specific treatment that selectively kills various types of malignant cells. We used CAP-activated media (PAM) to utilize a range of the generated short- and long-lived reactive species. Specific antibodies, small molecule inhibitors and CRISPR/Cas9 gene-editing approaches showed an essential role for receptor tyrosine kinases, especially epidermal growth factor (EGF) receptor, in mediating triple negative breast cancer (TNBC) cell responses to PAM. EGF also dramatically enhanced the sensitivity and specificity of PAM against TNBC cells. Site-specific phospho-EGFR analysis, signal transduction inhibitors and reconstitution of EGFR-depleted cells with EGFR-mutants confirmed the role of phospho-tyrosines 992/1173 and phospholipase C gamma signaling in up-regulating levels of reactive oxygen species above the apoptotic threshold. EGF-triggered EGFR activation enhanced the sensitivity and selectivity of PAM effects on TNBC cells. The proposed approach based on the synergy of CAP and EGFR-targeted therapy may provide new opportunities to improve the clinical management of TNBC.
Competing Interests: Declaration of competing interest Several patents are relevant to this work. (1) “plasma gun for treating tumors in vivo and use method thereof” Dai X; (2) “classifying epidermal growth factor receptor positive tumor into subtype e.g. epidermal growth factor receptor antagonist sensitive subtype” Simpson F, Saunders NA; (3) “composition useful in kit for treating tumor, preferably cell surface antigen positive tumor e.g. cancerous tumors, comprises antibody that binds to cell surface antigen of tumor and inhibitor of receptor mediated endocytosis” Simpson F, Saunders NA; (4) “Methods for Classifying Tumors and Uses Therefor” Simpson F, Leftwich SR.
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